Atopaxar: A review of its mechanism of action and role in patients with coronary artery disease

Future Cardiology

Volumn 8, Issue 4, 2012, Pages 503-511

  Rollini, Fabiana ^a   Tello Montoliu, Antonio ^a   Angiolillo, Dominick J ^a  

^a UNIVERSITY OF FLORIDA COLLEGE OF MEDICINE   (United States)

Author keywords

acute coronary syndrome; antiplatelet therapy; atopaxar; PAR 1 antagonist

Indexed keywords

ACETYLSALICYLIC ACID; ANTITHROMBOCYTIC AGENT; ATOPAXAR; CLOPIDOGREL; FRI 171113; PRASUGREL; PROTEINASE INHIBITOR; SCH 205381; SCH 205831; SCH 602539; THROMBIN; TICAGRELOR; TICLOPIDINE; UNCLASSIFIED DRUG; VORAPAXAR;

ACUTE CORONARY SYNDROME; ALANINE AMINOTRANSFERASE BLOOD LEVEL; ARTERY THROMBOSIS; ASPARTATE AMINOTRANSFERASE BLOOD LEVEL; BLEEDING; CLINICAL TRIAL; CORONARY ARTERY DISEASE; DRUG HALF LIFE; DRUG STRUCTURE; HUMAN; LOADING DRUG DOSE; NONHUMAN; PERCUTANEOUS CORONARY INTERVENTION; PRIORITY JOURNAL; QT PROLONGATION; REVIEW; RISK; SIDE EFFECT; SINGLE DRUG DOSE; THROMBOCYTE ACTIVATION; THROMBOSIS;

ACUTE CORONARY SYNDROME; ANIMALS; CORONARY ARTERY DISEASE; CORONARY THROMBOSIS; HUMANS; IMINES; PLATELET ACTIVATION; PLATELET AGGREGATION INHIBITORS; PYRIDINES; RECEPTORS, THROMBIN; TICLOPIDINE;

EID: 84864862425     PISSN: 14796678     EISSN: 17448298     Source Type: Journal    
DOI: 10.2217/fca.12.35     Document Type: Review

References (57)

1. Libby P. Current concepts of the pathogenesis of the acute coronary syndromes. Circulation 104, 365-372 (2001).
2. Braunwald E, Angiolillo D, Bates E et al. The problem of persistent platelet activation in acute coronary syndromes and following percutaneous coronary intervention. Clin. Cardiol. 31, 17-20 (2008).
3. Angiolillo DJ, Ueno M, Goto S. Basic principles of platelet biology and clinical implications. Circ. J. 74, 597-607 (2010).
4. Furie B, Furie BC. Mechanisms of thrombus formation. N. Engl. J. Med. 359, 938-949 (2008).
5. Davi G, Patrono C. Platelet activation and atherothrombosis. N. Engl. J. Med. 357, 2482-2494 (2007).
6. Offermanns S. Activation of platelet function through G protein-coupled receptors. Circ. Res. 99, 1293-1304 (2006).
7. Meadows TA, Bhatt DL. Clinical aspects of platelet inhibitors and thrombus formation. Circ. Res. 100, 1261-1275 (2007).
8. Angiolillo DJ, Capodanno D, Goto S. Platelet thrombin receptor antagonism and atherothrombosis. Eur. Heart J. 31, 17-28 (2010).
9. Steinhoff M, Buddenkotte J, Shpacovitch V et al. Proteinase-activated receptors: Transducers of proteinase-mediated signaling in inf lammation and immune response. Endocr. Rev. 26, 1-43 (2005).
10. Patrono C, García Rodríguez LA, Landolf i R et al. Low-dose aspirin for the prevention of atherothrombosis. N. Engl. J. Med. 353, 2373-2383 (2005).
11. Wallentin LC. Aspirin (75 mg/day) after an episode of unstable coronary artery disease: Long-term effects on the risk for myocardial infarction, occurrence of severe angina and the need for revascularization. Research Group on instability in coronary artery disease in Southeast Sweden. J. Am. Coll. Cardiol. 18, 1587-1593 (1991).
12. Baigent C, Blackwell L, Collins R et al.; Antithrombotic Trialists' (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: Collaborative meta-analysis of individual participant data from randomized trials. Lancet 373, 1849-1860 (2009).
13. Anderson JL, Adams CD, Antman EM et al. 2011 Writing group members; ACCF/AHA task force members. 2011 ACCF/AHA focused update incorporated into the ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: A report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 123, 426-579 (2011).
14. Levine GN, Bates ER, Blankenshi JC et al. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention. A Report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines and the Society for cardiovascular angiography and interventions. J. Am. Coll. Cardiol. 58, E44-E122 (2011).
15. Vivas D, Angiolillo DJ. Platelet P2Y12 receptor inhibition: An update on clinical drug development. Am. J. Cardiovasc. Drugs 10, 217-226 (2010).
16. Bertrand ME, Rupprecht HJ, Urban P et al.; CLASSICS Investigators. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: The clopidogrel aspirin stent international cooperative study (CLASSICS). Circulation 102, 624-629 (2000).
17. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E et al. Variability in individual responsiveness to clopidogrel: Clinical implications, management, and future perspectives. J. Am. Coll. Cardiol. 49, 1505-1516 (2007).
18. Angiolillo DJ, Ferreiro JL. Platelet adenosine diphosphate P2Y12 receptor antagonism: Benefits and limitations of current treatment strategies and future directions. Rev. Esp. Cardiol. 63, 60-76 (2010).
19. Capodanno D, Dharmashankar K, Angiolillo DJ. Mechanism of action and clinical development of ticagrelor, a novel platelet ADP P2Y12 receptor antagonist. Expert Rev. Cardiovasc. Ther. 8, 151-158 (2010).
20. Tomasello SD, Tello-Montoliu A, Angiolillo DJ. Prasugrel for the treatment of coronary thrombosis: A review of pharmacological properties, indications for use and future development. Expert Opin. Invest. Drugs 20, 119-133 (2011).
21. Wiviott SD, Braunwald E, McCabe CH et al.; TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N. Engl. J. Med. 357, 2001-2015 (2007).
22. Wallentin L, Becker RC, Budaj A et al.; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N. Engl. J. Med. 361, 1045-1057 (2009).
23. Mehran R, Pocock S, Nikolsky E et al. Impact of bleeding on mortality after percutaneous coronary intervention results from a patient-level pooled analysis of the REPLACE-2 (randomized evaluation of PCI linking angiomax to reduced clinical events), ACUITY (acute catheterization and urgent intervention triage strategy), and HORIZONS-AMI (harmonizing outcomes with revascularization and stents in acute myocardial infarction) trials. JACC Cardiovasc. Interv. 4, 654-664 (2011).
24. Michelson AD, Frelinger AL 3rd, Braunwald E et al.; TRITON-TIMI 38 Investigators. Pharmacodynamic assessment of platelet inhibition by prasugrel vs. clopidogrel in the TRITON-TIMI 38 trial. Eur. Heart J. 30, 1753-1763 (2009).
25. Storey RF, Angiolillo DJ, Patil SB et al. Inhibitory effects of ticagrelor compared with clopidogrel on platelet function in patients with acute coronary syndromes: The PLATO (PLATelet inhibition and patient Outcomes) PLATELET substudy. J. Am. Coll. Cardiol. 56, 1456-1462 (2010).
26. Coughlin SR. Protease-activated receptors in hemostasis, thrombosis and vascular biology. J. Thromb. Haemost. 3, 1800-1814 (2005).
27. Kahn ML, Nakanishi-Matsui M, Shapiro MJ et al. Protease-activated receptors 1 and 4 mediate activation of human platelets by thrombin. J. Clin. Invest. 103, 879-887 (1999).
28. Ueno M, Ferreiro JL, Angiolillo DJ. Mechanism of action and clinical development of platelet thrombin receptor antagonists. Expert Rev. Cardiovasc. Ther. 8, 1191-1200 (2010).
29. Xu WF, Andersen H, Whitmore TE et al. Cloning and characterization of human protease-activated receptor 4. Proc. Natl Acad. Sci. USA 95, 6642-6646 (1998).
30. Lova P, Canobbio I, Guidetti GF et al. Thrombin induces platelet activation in the absence of functional protease activated receptors 1 and 4 and glycoprotein Ib-IX-V. Cell Signal. 22, 1681-1687 (2010).
31. Henriksen RA, Hanks VK. PAR-4 agonist AYPGKF stimulates thromboxane production by human platelets. Arterioscler. Thromb. Vasc. Biol. 22, 861-866 (2002).
32. Covic L, Singh C, Smith H et al. Role of the PAR4 thrombin receptor in stabilizing platelet-platelet aggregates as revealed by a patient with Hermansky-Pudlak syndrome. Thromb. Haemost. 87, 722-727 (2002).
33. Lova P, Campus F, Lombardi R et al. Contribution of protease-activated receptors 1 and 4 and glycoprotein Ib-IX-V in the G(i)-independent activation of platelet Rap1B by thrombin. J. Biol. Chem. 279, 25299-25306 (2004).
34. Smith CC, Wilson AP, Prichard BN et al. Stimulus-induced release of endogenous catecholamines from human washed platelets. Clin. Sci. (Lond.) 70, 495-500 (1986).
35. Henn V, Slupsky JR, Grafe M et al. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 391, 591-594 (1998).
36. Offermanns S, Toombs CF, Hu YH et al. Defective platelet activation in G a(q)-deficient mice. Nature 389, 183-186 (1997).
37. Andersen H, Greenberg DL, Fujikawa K et al. Protease-activated receptor 1 is the primary mediator of thrombin-stimulated platelet procoagulant activity. Proc. Natl Acad. Sci. USA 96, 11189-11193 (1999).
38. Goldsack NR, Chambers RC, Dabbagh K et al. Thrombin. Int. J. Biochem. Cell. Biol. 30, 641-646 (1998).
39. Leger AJ, Jacques SL, Badar J et al. Blocking the protease-activated receptor 1-4 heterodimer in platelet-mediated thrombosis. Circulation 113, 1244-1254 (2006).
40. Chintala M, Ahn H, Foster C et al. Antithrombotic effects of SCH 205831: A potent, selective and orally active antagonist of the PAR-1 thrombin receptor. J. Thromb. Haemost. 3(Suppl. 1) (2005) (Abstract OR286).
41. Chackalamannil S, Xia Y, Greenlee WJ et al. Discovery of potent orally active thrombin receptor (protease activated receptor 1) antagonists as novel antithrombotic agents. J. Med. Chem. 48, 5884-5887 (2005).
42. Chintala M, Strony J, Yang B et al. SCH 602539, a protease-activated receptor-1 antagonist, inhibits thrombosis alone and in combination with cangrelor in a Folts model of arterial thrombosis in cynomolgus monkeys. Arterioscler. Thromb. Vasc. Biol. 30, 2143-2149 (2010).
43. Kato Y, Kita Y, Hirasawa-Taniyama Y et al. Inhibition of arterial thrombosis by a protease-activated receptor 1 antagonist, FR171113, in the guinea pig. Eur. J. Pharmacol. 473, 163-169 (2003).
44. Kogushi M, Matsuoka T, Kawata T et al. The novel and orally active thrombin receptor antagonist E5555 (atopaxar) inhibits arterial thrombosis without affecting bleeding time in guinea pigs. Eur. J. Pharmacol. 657, 131-137 (2011).
45. Kogushi M, Yokohama H, Kitamura S et al. Effects of E5555, a protease activated receptor-1 antagonist, on the inflammatory markers in vitro. J. Thromb. Haemost. 5 (Suppl. 2) (2007) (Abstract P-M-059).
46. Kai Y, Hirano K, Maeda Y et al. Prevention of the hypercontractile response to thrombin by proteinase-activated receptor-1 antagonist in subarachnoid hemorrhage. Stroke 38, 3259-3265 (2007).
47. Hamilton JR, Cornelissen I, Coughlin SR. Impaired hemostasis and protection against thrombosis in protease-activated receptor 4-deficient mice is due to lack of thrombin signaling in platelets. J. Thromb. Haemost. 2, 1429-1435 (2004).
48. Derian CK, Damiano BP, Addo MF et al. Blockade of the thrombin receptor protease-activated receptor-1 with a small-molecule antagonist prevents thrombus formation and vascular occlusion in nonhuman primates. J. Pharmacol. Exp. Ther. 304, 855-861 (2003).
49. Matsuoka T, Kogushi M, Kawata T et al. Inhibitory effect of E5555, an orally active thrombin receptor antagonist, onintimal hyperplasia following balloon injury. J. Am. Coll. Cardiol. 43, 68A (2004).
50. Marion A, Reyes J, Chen H et al. Safety, pharmacokinetics, and pharmacodynamics of ascending multiple oral doses of a new protease activated receptor-1 inhibitor in healthy volunteers. Presented at: 35th Annual Meeting of the American College of Clinical Pharmacology. Cambridge, MA, USA, 17-19 September 2006.
51. Takeuchi M, Kageyama M, Kitamura S et al. Pharmacodinamics and safety of a novel protease activated receptor-1 antagonist E5555 in healthy volunteers. Eur. Heart J. 28(Suppl. 1), (2007) (Abstract Vienna 264).
52. Serebruany VL, Kogushi M, Dastros-Pitei D et al. The in-vitro effects of E5555, a protease-activated receptor (PAR)-1 antagonist, on platelet biomarkers in healthy volunteers and patients with coronary artery disease. Thromb. Haemost. 102, 111-119 (2009).
53. Goto S, Ogawa H, Takeuchi M et al.; J-LANCELOT (Japanese-Lesson from Antagonizing the Cellular Effect of Thrombin) Investigators. Double-blind, placebo-controlled Phase II studies of the protease-activated receptor 1 antagonist E5555 (atopaxar) in Japanese patients with acute coronary syndrome or high-risk coronary artery disease. Eur. Heart J. 31, 2601-2613 (2010).
54. O'Donoghue ML, Bhatt DL, Wiviott SD et al.; LANCELOT-ACS Investigators. safety and tolerability of atopaxar in the treatment of patients with acute coronary syndromes the lessons from antagonizing the cellular effects of thrombin-acute coronary syndromes trial. Circulation 123, 1843-1853 (2011).
55. Wiviott SD, Flather MD, O'Donoghue ML et al.; LANCELOT-CAD Investigators. Randomized trial of atopaxar in the treatment of patients with coronary artery disease: The lessons from antagonizing the cellular effect of thrombin-coronary artery disease trial. Circulation 123, 1854-1863 (2011).
56. Tricoci P, Huang Z, Held C et al; The TRACER Investigators. Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. N. Engl. J. Med. 366, 20-33 (2012).
57. Morrow DA, Braunwald E, Bonaca MP et al.; The TRA 2P-TIMI 50 Steering Committee and Investigators. Vorapaxar in the secondary prevention of atherothrombotic events. N. Engl. J. Med. 366(15), 1404-1413 (2012).